This invention relates to a composition and a method for oral transmucosal delivery of active substances to a human or animal via the inner buccal cavity. More particularly, this invention relates to an improved dosage form which can easily adhere to the inner buccal cavity and sustain transmucosal release of drugs, odorants or any other ingredients and exhibit the activity effectively.
The sustained delivery of certain active substances, especially ionic peptide-based drugs, presents one of the greatest challenges in pharmaceutical science. Oral administration of pharmaceutical compositions has some drawbacks. For instance, it is difficult to keep the medicament at the desired location so that it can be absorbed, it is easily metabolized in the liver, and it is easily decomposed in the stomach. Accordingly, there has been much interest in the use of the mucosal lining of body cavities, for example the oral cavity, as the site of administration of active substances. Both the buccal and sublingual membranes offer advantages over other routes for administration. For example, drugs administered through the buccal and sublingual routes have a rapid onset of action, reach high levels in the blood, avoid the first-pass effect of hepatic metabolism, and avoid exposure of the drug to fluids of the gastrointestinal tract. Additional advantages include easy access to the membrane sites so that an active substance containing device can be applied, localized, and removed easily. Further, there is good potential for prolonged delivery through the mucosal membrane. M. Rathbone & J. Hadgraft, 74 Int'l J. of Pharmaceutics 9 (1991).
The sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth, whereas the buccal mucosa constitutes the lining of the cheek. The sublingual mucosa is relatively more permeable than the buccal mucosa, thus giving rapid absorption and acceptable bioavailability of many active substances. Furthermore, the sublingual mucosa is convenient, accessible, and generally well accepted. This route has been investigated clinically for the delivery of a substantial number of drugs. It is the preferred route for administration of nitroglycerin and is also used for buprenorphine and nifedipine. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1 (1992).
The buccal mucosa is less permeable than the sublingual mucosa. The rapid absorption and high bioavailabilities seen with sublingual administration of drugs is not generally provided to the same extent by the buccal mucosa. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. (1992) at 2. The permeability of the oral mucosa is probably related to the physical characteristics of the tissues. The sublingual mucosa is thinner than the buccal mucosa, thus permeability is greater for the sublingual tissue. The palatal mucosa is intermediate in thickness, but is keratinized thus lessening its permeability, whereas the other two tissues are not.
The ability of molecules to permeate through the oral mucosa appears to be related to molecular size, lipid solubility, ionization and many other factors. Small molecules, less than about 100 daltons, appear to cross the mucosa rapidly. As molecular size increases permeability decreases rapidly. Lipid-soluble compounds are more permeable through the mucosa than are non-lipid-soluble molecules. In this regard, the relative permeabilities of molecules seems to be related to their partition coefficients. The degree of ionization of molecules, which is dependent on the pK.sub.a of the molecule and the pH at the membrane surface, also greatly affects permeability of the molecules. Maximum absorption occurs when molecules are unionized or neutral in electrical charge and absorption decreases as the degree of ionization increases. Therefore, charged drugs, such as ionized polypeptide based drugs, present a significant challenge to absorption through the oral mucosa.
For a number of practical purposes it can be useful to affix a device containing an active substance within a mucosal-lined body cavity, such as the oral cavity. For example, conventional forms of substance delivery such as a lozenge, troche, breath freshener, mouth wash or spray work by shedding or admixing the substance into the saliva, which bathes the tissues of the oral cavity and throat as it passes posteriorly towards the esophagus. Such forms remain in the oral cavity only for short periods of time, generally not more than about 10 to 20 minutes, and they cannot always provide for effective sustained delivery of the substance. Moreover, the presence of a lozenge or troche in the user's mouth can be annoying or distracting, and may interfere with speech or with the ingestion of fluids. Holding the lozenge in the mouth to avoid either swallowing it or spitting it out requires conscious effort, and inadvertent loss can be embarrassing.
There are numerous instances where the active substance is intended for use at the site of delivery rather than absorption through mucosal membranes for systemic use. For example breath fresheners for the treatment of, or as a prophylactic against, halitosis, or agents for the treatment of xerostomia (dryness of the mouth) function directly in the oral cavity rather than through absorption. However, it would be desirable to have such agents held in place in the oral cavity to avoid the problems associated with lozenges or troches as noted above.
Various bioadhesives have been proposed for use in establishing adhesive contact with mucosal surfaces. See, for example, Biegajski, U.S. Pat. No. 5,700,478; Lowey, U.S. Pat. No. 4,259,314; Lowey, U.S. Pat. No. 4,680,323; Yukimatsu et al., U.S. Pat. No. 4,740,365; Kwiatek et al., U.S. Pat. No. 4,573,996; Suzuki el al., U.S. Pat. No. 4,292,299; Suzuki et al., U.S. Pat. No. 4,715,369; Mizobuchi et al., U.S. Pat. No. 4,876,092; Fankhauser et al, U.S. Pat. No. 4,855,142; Nagai et al., U.S. Pat. No. 4,250,163; Nagai et al., U.S. Pat. No. 4,226,848; Browning, U.S. Pat. No. 4,948,580; Schiraldi et al., U.S. Reissue Patent Re.33,093; and J. Robinson, 18 Proc. Intern. Symp. Control. Rel. Bioact. Mater. 75 (1991). Typically, these adhesives consist of a matrix of a hydrophilic, e.g., water soluble or swellable, polymer or mixture of polymers which can adhere to wet mucosal surfaces. Such polymers are inclusive of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, gaur-gum, polyvinyl pyrrolidone, pectins, starches, gelatin, casein, acrylic acid, acrylic acid esters, acrylic acid copolymers, vinyl polymers, vinyl copolymers, vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers, and the like. These adhesives may be formulated as ointments, thin films, tablets, troches, and other forms. Often, these adhesives have had medicaments mixed therewith to effectuate slow release or local delivery of a drug.
However, these known bioadhesives have several drawbacks. For example, adhesives in the form of pastes, creams or ointments are messy and inconvenient to use, and generally adhere poorly or not at all and are not suitable for extended periods of use. Some forms of adhesives, such as Carbopol (carboxyvinyl polymers), are not water soluble thus leave a tacky, greasy residue in the oral cavity of the wearer, and can cause sustained oral irritation. In addition, Carbopol based adhesives are ionic polymers which interact with ionic active substances, such as ionic polypeptide based drugs, and can inhibit absorption of such active substances. On the other hand, some forms of adhesives remain in the oral cavity for only short periods of time, e.g. generally not more than about 10 or 20 minutes, and therefore cannot provide for delivery of a substance over an extended period of time.
Improved adhesives have been attained by using sodium alginate to overcome some of the problems associated with Carbopol based adhesives. However, sodium alginate is also an anionic polymer that shows ionic interaction with cationic active substances. Therefore, to formulate an adhesive having little or no interaction with ionic active substances, such as ionic polypeptide based drugs, would be highly desirable.
It has been discovered that polyvinyl pyrrolidone (PVP), without the presence of a plasticizer, used alone or in combination with other polymers or copolymers, has sufficient adhesion properties to the oral mucosa and also to polyacrylic denture materials to function surprisingly well to adhere devices containing active substances to the oral cavity. Since PVP is a non-ionic compound, a PVP-based mocoadhesive does not interact with ionic active substances. Moreover, PVP-based adhesives show a significant reduction in irritation of mucosa in human trials, compared to Carbopol-based adhesives. Although plasticized PVP has been used as an ingredient of bioadhesive compositions in prior art, a non-plasticized PVP based mucoadhesive has not heretofore been taught or suggested. In addition, the non-plasticized PVP based mucoadhesives of this invention show an improved stability when compared with prior mucoadhesives.
U.S. Pat. No. 4,740,365 discloses a sustained-release mucoadhesive preparation that may consist of one or two layers. However, the mucoadhesive layer is always a combination of two polymers components with a ratio of 95:5 to 5:95. One polymer component comprises one or more polymers selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and an alternating copolymer of maleic anhydride and methyl vinyl ether. The other polymer component comprises one or more polymers selected from polyacrylic acid or a salt thereof. One aspect of the invention is to combine the two polymer components to maximize adhesive properties. U.S. Pat. No. 5,700,478 discloses a water-soluble pressure-sensitive adhesive including a water-soluble polymer that is made tacky at room temperature by addition of a water-soluble plasticizer that is miscible with the polymer. The presence of the plasticizer negatively affects the palatability and stability of the mucoadhesive. In addition to undesirable interaction with the ionic active substances, the presence of plasticizers or other ionic polymers in the mucoadhesive may also cause undesirable wearing properties or irritation.
Therefore, there is a need for a mucoadhesive that does not interact with ionic active substances and does not affect the palatability of the adhesive. The non-plasticized PVP-based mucoadhesive of the present invention also simplifies and reduces the cost of manufacture. In addition, a non-plasticized PVP-based mucoadhesive of this invention also reduces the unpleasant flavor and oral irritation associated with plasticizers or other copolymers.